PRONGF/NGF and nerve infiltration in prostate and breast cancer

Nerve fibre infiltration has recently been demonstrated as paramount to the tumor microenvironment and essential to cancer progression. However, it has not been clearly elucidated what attracts neuronal fibres into tumors. A plausible explanation is the overexpression of neurotrophic factors, such as nerve growth factor (NGF) or its precursor proNGF. These proteins are distinctively involved in neuronal survival/apoptosis through interactions with specific membrane receptors such as TrkA, p75^NTR and sortilin. This thesis aims to show whether proNGF/NGF overexpression drives nerve infiltration in prostate and breast cancer. What has been showed herein is that the overexpression of proNGF in a cohort of 104 prostate cancer cases, observed using immunohistochemistry has a direct correlation with the aggressiveness of prostate cancer (t_B= 0.51). A 60-kilodalton proNGF was detected by western blotting of prostate cancer cells, whereas the proteolytically processed NGF was not detected. In addition, we performed an in vitro co-culture of prostate cancer cells with neuronal cells and demonstrated the neurotrophic effect of prostate cancer cells to stimulate axonogenesis via the secretion of proNGF. Furthermore, in breast cancer we have shown nerve fibre infiltration by immunohistochemistry using the neuronal marker protein gene product (PGP) 9.5. Nerve infiltration was found to be associated with NGF expression and lymph node invasion. Secreted NGF was detected by dot blot analysis of conditioned medium from breast cancer cells. Interestingly, in vitro co-culture assays demonstrated that NGF secreted from breast cancer cells stimulated neurite outgrowth of neuronal cells, and that this effect could be inhibited by using an anti-NGF blocking antibody, thus supporting the neurotrophic potential of these cells. In conclusion, we have shown that proNGF is a driver of nerve infiltration in prostate cancer and that a similar phenomenon occurs in breast cancer via NGF. This study suggests new avenues for inhibiting prostate and breast cancer growth and metastasis by inhibiting axonogenesis via the targeting of proNGF and NGF.